Coronaviruses may cause disease in humans (e.g. the severe acute respiratory syndrome, SARS) and in animals. Coronaviruses primarily infect the upper respiratory and gastrointestinal tract of mammals and birds. Four to five different currently known strains of coronaviruses infect humans. The most publicized human coronavirus, SARS-CoV which causes SARS, has a unique pathogenesis because it causes both upper and lower respiratory tract infections and can also cause gastroenteritis. Coronaviruses are believed to cause a significant percentage of all common colds in human adults. Coronaviruses cause colds in humans primarily in the winter and early spring seasons. The significance and economic impact of coronaviruses as causative agents of the common cold are hard to assess because, unlike rhinoviruses (another common cold virus), human coronaviruses are difficult to grow in the laboratory.
Coronaviruses also cause a range of diseases in farm animals and domesticated pets, some of which can be serious and are a threat to the farming industry. Economically significant coronaviruses of farm animals include porcine coronavirus (transmissible gastroenteritis, TGE) and bovine coronavirus, which both result in diarrhea in young animals. Feline enteric coronavirus is a pathogen of minor clinical significance, but spontaneous mutation of this virus can result in feline infectious peritonitis (FIP), a disease associated with high mortality. In cats, two coronaviruses are described: feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV). These coronaviruses are spread world-wide and infect not only domestic cats but also all other members of the Felidae family. An infection with FIPV causes a severe pleuritis/peritonitis which mostly leads to death. Ill cats usually have very high titers of FIPV-specific antibodies. However, these antibodies are not able to block infection even though infected target cells, blood monocytes, do express viral proteins in their plasma membrane allowing antibody-dependent complement mediated cell lysis. Also cell mediated immunity is impaired as cytotoxic T-cells are depleted during infection. Moreover, some vaccines against feline coronaviruses have been proven to enhance disease when vaccinated animals were exposed to the wild-type virus, and thus anti-body enhancement of disease is a potential risk of coronavirus diseases in animals or humans (Pedersen, N. and Boyle, J. (1980)., Vennema, H. et al. (1990a)., Pedersen, N. and Black, J. (1983) McArdle, F., et al. (1992)).
Drugs with proven efficacy against coronaviruses are currently missing, and there is a clear need to develop effective drugs against coronaviruses. It is accordingly an object of the present invention to provide models and methods to come and identify anti-coronaviral drugs, as well as to the use thereof in treating corona viral infections, such as for example caused by the feline infectious peritonitis virus (FIPV), and in particular in the treatment of FIP.
It has now surprisingly been found that MLCK is involved as a positive regulator in the internalization pathway of viral particles or of viral proteins upon binding of anti-viral antibodies in the host cell, and accordingly an important element in the viral infection pathways. As demonstrated in the examples hereinafter, it has now been found that using specific MLCK inhibitors it is possible to interfere with the internalization of viruses in the host and with the internalization of viral proteins upon binding of anti-viral antibodies in the host cell. The latter is an immune evasion process by which the infected cells can hide itself from the immune system of the host.
Where it has previously been shown that kinase inhibitors can interfere with the viral replication of Rhabdoviridae (Kim Young-Sook and Kawai Akihiko, (1998)), with for example no observed effect in the replication of Togaviridae, said earlier disclosure did not suggest MLCK as a target for inhibitors directed against the aforementioned internalization processes. The present finding accordingly provides a novel anti-viral treatment, which is particularly useful in treating viral infections of virus families selected from the group consisting of Coronaviridae, Nidovirales, Herpesviridae, Orthomyxoviridae, Retroviridae, and Flaviviridae; in particular in the treatment of viral infection of Coronaviridae such as for example caused by the feline infectious peritonitis virus (FIPV) or the feline enteric coronavirus (FECV).